OR02-3 Gender Modulates the Adrenal and Vascular Responses to Angiotensin II

Program: Abstracts - Orals, Poster Previews, and Posters
Session: OR02-Renin-Angiotensin-Aldosterone - Bench to Bedside
Basic/Translational
Friday, April 1, 2016: 11:45 AM-1:15 PM
Presentation Start Time: 12:15 PM
Room 156 (BCEC)

Health Disparities
Mohammad Zaki Shukri*1, Richard H Karas2, Luminita H Pojoga3, Iris Z Jaffe2, Gail K Adler3, Gordon H Williams3 and Jose R Romero3
1Brigham and Women's Hospital, Boston, MA, 2Tufts Medical Center, Boston, MA, 3Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Cardiovascular diseases (CVD) and hypertension are more common in young males when compared to premenopausal females; a difference that disappears following menopause. Sex differences in blood pressure also have been reported in rodent models of hypertension. In addition, our group reported that estradiol-deficient, ovariectomized rats are protected against cardiovascular and renal damage mediated by aldosterone (Aldo) and mineralocorticoid receptor (MR) activation; estradiol replacement restores damage. We tested the hypothesis that sex affects the adrenal and vascular responses to angiotensin II (AngII). We studied 293 female and 447 male human subjects from the Hypertensive Pathotype (HyperPATH) study who were carefully monitored and on controlled high- and low-salt diets for one week. We measured plasma Aldo and systolic blood pressure (BP) before and after in vivo infusion of AngII and calculated ΔAldo and ΔBP. Our results show that ΔAldo was significantly greater in female than in male subjects on a low-salt diet (22.9 ± 13.0 vs 15.8 ± 9.98 ng/dL, respectively; P<0001 adjusted for age, serum cortisol, plasma renin activity, K+, and urinary K+) and on a high-salt diet (9.21 ± 5.85 vs 7.63 ± 5.12 ng/dL; P<0.0001 adjusted). Even when assessed by menopausal status (age >50 yr), the differences persisted. These events were associated with a greater ΔBP in females than males on a low salt diet (17.8 ± 13.7 vs 14.4 ± 11.4 mmHg, respectively; P<0.001 adjusted). These data indicate that females show greater adrenal and vascular responses to infused AngII than do males. To assess potential mechanisms for these gender differences, we studied a hypertensive rodent model characterized by low nitric oxide (NO) and increased AngII to mimic the hypertensive milieu. Male and female wistar rats were maintained on a liberal salt diet and given N{omega}-nitro-L-arginine-methyl-ester (L-NAME) to block NO synthase activity for 14 days with AngII administered on the last 3 days. Urinary and plasma Aldo levels were higher in L-NAME/AngII-treated female rats as compared with L-NAME/AngII-treated male rats (n=6/group; P<0.01). Systolic blood pressures were similar in male and female rats. However, treatment with eplerenone (100 mg/kg), an MR antagonist, led to significant reductions in BP in female but not male rats (n=6/group; P<0.05). In addition, the degree of myocardial damage and proteinuria induced by L-NAME/AngII treatment was greater in female versus male rats (n=8/group, P<0.05). Eplerenone protected female and male rats from L-NAME/AngII induced cardiac and renal damage to a similar extent. These results suggest that under conditions of low NO and high AngII, Aldo-mediated renal and cardiac damage is greater in female rats than in male rats despite similar BP levels. Thus we posit that Aldo/MR activation status may, in part, explain the varying effects of estrogen on CVD in women.

Nothing to Disclose: MZS, RHK, LHP, IZJ, GKA, GHW, JRR

*Please take note of The Endocrine Society's News Embargo Policy at https://www.endocrine.org/news-room/endo-annual-meeting/pr-resources-for-endo

Sources of Research Support: NIH Grants: R01-HL114765 and T32-HL007609 awarded to GHW, K24-HL103845 awarded to GKA and R01-HL096518 awarded to JRR.